Medulloblastoma is among the most malignant of the pediatric brain tumors, having an average 5-year survival rate of only 50%. Medulloblastoma is believed to arise mostly from the undifferentiated neural stem cells (NSCs) in the external granule layer (EGL) cells of the cerebellum. Although several mechanisms have been found to be involved in medulloblastoma tumorigenesis, each of them represents only a small fraction of all human medulloblastoma tumors. Thus, one challenge for studies of medulloblastoma is understanding the mechanisms that regulate most of these tumors. Our previous studies with human medulloblastoma tumor samples, a tissue culture systemof an NSC line, and an orthotopic intracranial mouse model system suggested a novel convergence of known medulloblastoma mechanisms via REST/NRSF as a cause for most medulloblastoma tumors. In this grant, we propose to examine the physiological relevance of the cooperation of REST/NRSF, c-Myc, the beta-catenin pathway, and the Shh pathway in producing a medulloblastoma phenotype by using two in vivo models, RCAS/Ntv-a mice (somatic gene transfer) and a transgenic mouse system (germline gene transfer). We also propose to examine the role of the central molecule REST/NRSF as a potential target for medulloblastoma therapy. Thus, by combining developmental biology, transcription biology, cancer biology, and mouse models, the proposed studies will yield critical information towards our long-term goal of studying the genesis of medulloblastoma and will produce mechanism-based animal models that can be used to identify new, physiologically relevant targets for therapy and to test both existing and new drugs for medulloblastoma. The experiments proposed here are in accordance with the recommendations of the NCI Brain Tumor Progress Review Group.